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| Status |
Public on Apr 07, 2020 |
| Title |
Clinical and biological implications of target occupancy in chronic lymphocytic leukemia treated with acalabrutinib |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in chronic lymphocytic leukemia (CLL). Target occupancy has been measured as a pharmacodynamic parameter in clinical studies of covalent BTK inhibitors. However, the kinetics of BTK turnover, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remains undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily or 200 mg once daily in 48 patients with relapsed/refractory or high-risk treatment naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% CI 78.9%, 99.9%) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI 70.0%, 97.8%) with twice daily dosing and an ORR of 79.2% (95% CI 57.9%, 92.9%) and an estimated PFS rate at 24 months of 87.2% (95% CI 57.2%, 96.7%) with once daily dosing. BTK resynthesis was faster in CLL than in healthy volunteers. Twice daily dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared to once daily dosing. Additional follow-up is required to address the impact of dosing schedule and BTK occupancy on long-term clinical outcomes.
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| Overall design |
RNA sequencing of CD19+ peripheral blood mononuclear cells and lymph node core biopsies before and during treatment with acalabrutinib
ACP = acalabrutinib
BID = twice daily
QD = once daily
D3/4/5 = day 3/4/5 of treatment
C1/6 = after cycle 1/6 of treatment
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| |
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| Contributor(s) |
Sun C, Kendall E, Pirooznia M, Wiestner A |
| Citation(s) |
32202637 |
| |
| Submission date |
Aug 29, 2019 |
| Last update date |
Jun 02, 2021 |
| Contact name |
Mehdi Pirooznia |
| E-mail(s) |
pirooznia@gmail.com
|
| Phone |
410-340-6052
|
| Organization name |
National Institutes of Health
|
| Street address |
12 SOUTH DR
|
| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
|
| Samples (124)
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| Relations |
| BioProject |
PRJNA562903 |
| SRA |
SRP219651 |
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